This proposal provides a comprehensive plan for the career development of the applicant in cancer biomarker discovery and validation. Through mentored research, coursework and independent study, Dr. Van Poznak will develop collaborative relationships and methodologic skills to support her research agenda in pharmogenomics and toxicities of therapy. The didactic training in clinical trial design and ethics, pharmacogenomics and genetic analysis proposed will greatly expand the candidate's current training and research program. This proposal focuses on the use of novel technologies to improve assessment of risk of toxicities during cancer care, specifically by combining clinical and genetic data to establish an individualized patient specific profile of risk for developing osteonecrosis of the jaw (ONJ), an oral lesion with exposed, necrotic bone. These lesions are often associated with pain, swelling, and infection. ONJ may occur in 1- 10% of patients with cancer and bone metastases treated with intravenous nitrogen containing bisphosphonate therapy. The bisphosphonates decrease the risk of skeletal related events, such as fracture, by approximately one third and are routinely used in patients with cancer involving the bone. The overarching goal of this research proposal is to develop an index for estimating an individual's risk of developing ONJ. This index of risk will be created with the data generated from a multi-Institutional, Case Control study investigating single nucleotide polymorphisms (SNPs) within the target enzyme of the bisphosphonates, as well as investigate clinical and epidemiologic features associated with ONJ in patients with metastatic bone disease who have received intravenous bisphosphonate therapy. The identification of clinical and genetic markers correlated with risk of toxicity will lend insight into the etiology of ONJ and will provide patients and their health care providers a tool to assess risks of therapy on an individualized basis. The didactic training and mentored research activities will provide Dr Van Poznak the foundation for which she can generate highly competitive grant applications in the final years of the award and advance patient care through personalized medicine as it relates to cancer and the maintenance of bone integrity. RELEVANCE: Public Health: The constellation of clinical, epidemiologic and genetic factors will be used to generate an index of risk for the likelihood of developing osteonecrosis of the jaw (ONJ). Patients, dentists and medical oncologists will benefit from an instrument that will provide a personalized ONJ risk assessment.